Augmented SirT1 Activity Could Protect Against Osteoarthritis

Maintaining the activity of the enzyme SirT1 was suggested as a possible new approach to preventing or treating osteoarthritis (OA), a degenerative cartilage disease that affects millions of people around the world.

SirT1 is a histone deacetylase involved in numerous critical cell processes including DNA repair and apoptosis. Previous studies have shown that exposing human osteoarthritic chondrocytes (cartilage cells) to the cytokine TNFalpha generated a stable and enzymatically inactive 75 kDa form of SirT1 (75SirT1) via cathepsin B-mediated cleavage.

Because 75SirT1 was resistant to further degradation, investigators at the Hebrew University of Jerusalem (Israel) assumed it played a distinct role in osteoarthritis (OA) pathology, which they hoped to identify in a study that was published in the October 10, 2011, online edition of the journal Arthritis and Rheumatism.

Over the course of the study OA and normal human chondrocytes were analyzed for the presence of cathepsin B and 75SirT1. Confocal imaging of SirT1 monitored its subcellular trafficking following TNFalpha stimulation.

Results showed that that 75SirT1 was exported to the cytoplasm and colocalized with the mitochondrial membrane. Consistently, immunoprecipitation and immunoblot analyses revealed that 75SirT1 was enriched in mitochondrial extracts and associated with cytochrome C, following TNFalpha stimulation. Preventing nuclear export of 75SirT1 or reducing levels of SirT1 and 75SirT1 augmented chondrocyte apoptosis in the presence of TNFalpha. Cathepsin B and 75SirT1 were elevated in OA as compared to normal chondrocytes. Additional analyses showed that normal human chondrocytes exposed to OA-derived synovial fluid generated the 75SirT1 fragment.

The results indicated that 75SirT1 promoted chondrocyte survival following exposure to proinflammatory cytokines such as TNFalpha. Drug therapies directed at boosting SirT1 production have the potential to retard or reverse OA.

“Developing a combined strategy for diagnosis and treatment, based on these data, could provide an efficient alternative for joint replacement surgery and enable susceptible individuals to experience a better quality of life for years to come,” said senior author Dr. Mona Dvir-Ginzberg, lecturer in the Institute of Dental Sciences at the Hebrew University of Jerusalem.

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Hebrew University of Jerusalem